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The story of VIDEM began in 2014 with an idea for virus diagnostics that could be used to prepare for a pandemic. Dag Winkler, professor of physics, together with colleagues from Chalmers, Rise, KI, SciLifeLab, and Uppsala University, submitted a project proposal based on a technology called Rolling Circle Amplification (RCA). 
“The research project was funded by the Swedish Foundation for Strategic Research and lasted for 6 years. The project was concluded at the beginning of the Covid-19 pandemic when the need for reliable and accessible diagnostics became clearer than ever,” says Dag.
Researchers Dag Winkler and Sobhan Sepehri met students Maria Barklund and Petter Barreng through Chalmers Entrepreneurship School. In the fall of 2021, the company was founded together with Aldo Jesorka from Chalmers, as well as Maria Strömme and Teresa Zardán Gómez de la Torre from Uppsala University. 
"We saw great potential in making the project into a company, and we firmly believed in the vision and research behind it," says Maria.
Petter explains the technical aspect by combining the amplification and detection methods in a microfluidic lab-on-a-chip. The sample is inserted into the test cartridge (lab-on-a-chip), and the process of sample preparation, amplification, and detection occurs automatically. 
"There are many advantages to our technology, and the process applies to many different viruses and bacteria, creating opportunities to address various needs in the future," says Petter.
There are great ambitions for their product to be in every home and every hospital in the future. 
"The goal for VIDEM is to create global utility within 10 years and be used at home, even though our initial focus is primary health care. We have access to a lot at any time, but something as fundamental as testing oneself for various diseases is currently highly limited. The product we are developing should be so simple that it can be used anywhere," says Maria.
"Our vision is an important part of our company and our team-building. We strongly believe in our researchers, our team and our technology. The same applies to investors and when we recruit," says Petter.
Chalmers has been an important arena for developing the company. For example, the sensor is being developed in the cleanroom at MC2 in collaboration with other researchers. 
"We work closely with our co-founders from Chalmers and Uppsala University and have received grants from Vinnova for collaborations in technology development. The fact that the company originally comes from a university like Chalmers (and Uppsala) naturally strengthens the validity of the company," says Maria.
“VIDEM is an exciting project with many fascinating components and knowledgeable people involved. The company can contribute to society, and corporate formation is therefore important. Petter and Maria are also very successful in leading the company," says Dag.
<a href="/articles/s41598-022-21977-9/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics details</a>
Inflammation may contribute to excess mortality in rheumatoid arthritis (RA) patients
We investigated associations to all-cause mortality of the inflammation markers high-sensitivity C-reactive protein (CRP)
lactoferrin (neutrophil activation marker)
and neopterin (monocyte activation marker)
From the population-based Trøndelag Health Study (3rd wave 2006–2008)
316 RA patients and 43,579 controls were included
Lactoferrin and neopterin were quantified in a nested cohort (n = 283 RA patients
Follow-up was until death found by linkage to the Norwegian Cause of Death Registry or 31.12.2018
All-cause mortality was analyzed using Cox regression and Cox regression-based mediation analysis
p &lt; 0.001) were associated with all-cause mortality
The overall excess relative mortality risk of having RA was 38%
CRP ≥ 3 mg/L mediated approximately 1/4 of this risk (p &lt; 0.001)
p = 0.031) were associated with all-cause mortality
CRP levels ≥ 3 mg/L mediated approximately a quarter of the 38% excess relative all-cause mortality risk associated with RA
Using definitions of RA remission with emphasis both on joint status and the level of general inflammation may help guide the most efficient treatment regimens
we rather sought to use biomarkers to quantify associations of inflammation with all-cause mortality in RA patients compared to controls
Such quantification is possible using mediation analysis to investigate excess relative mortality in RA
The hypothesis for the present study was that biomarkers of inflammation representing different aspects of this complex process could act as proxies to quantify the importance of inflammation related to excess mortality in persons with RA compared to controls
The aims were therefore to investigate associations of CRP
and neopterin to all-cause mortality in RA patients and controls in a large population-based study
The Trøndelag Health Study (HUNT) is a population-based open cohort study performed in the northern part of Trøndelag county in Norway
All inhabitants aged ≥ 20 years are invited
The present study included participants from the 3rd wave
Serum samples stored at − 70 °C were provided from the HUNT Research Center
Written informed consent was obtained upon HUNT participation
The present study complies with the Declaration of Helsinki and was approved by the Norwegian Data Inspectorate and the Regional Committee for Medical and Health Research Ethics (#26264)
as part of the HUNT project HuLARS (HUNT Longitudinal Anklylosing spondylitis and Rheumatoid arthritis Study)
Participants in the main analysis including C-reactive protein
and the nested cohort study including the biomarkers C-reactive protein
Missing variables: C-reactive protein (1.5%)
HUNT3; 3rd wave of the Trøndelag Health Study (2006–2008)
Neopterin was analyzed using a commercial kit (Genway
All-cause mortality and causes of death were found through linkage of the study participants with the Norwegian Cause of Death Registry
which has &gt; 99% coverage for Norwegian citizens
Follow-up was from the inclusion date in HUNT3 until death or 31 December 2018
Data were analyzed using Stata (version 16.1
Two-tailed P-values &lt; 0.05 were considered statistically significant
Descriptive statistics are given as number (%) or median (95% CI) due to non-normal distributions in histograms of most variables
RA patients and controls were compared using the Chi-square test or Mann–Whitney U-test
Correlations among the three biomarkers at baseline were assessed using Spearman's rho
The binomial distribution was used to calculate 95% confidence intervals for mortality rates
Mortality was first analyzed in several steps using Cox regression
Observation time started on the date of inclusion in HUNT3
a very strong predictor of death was the time variable
ensuring that participants were always compared to controls of the same age
this design avoids problems with non-proportional hazards which often ensue with long observation times if age is used as an adjustment covariate instead of as the time variable
allowing for different baseline hazards in women and men
The Step2 models included either RA (Step2a) or CRP (Step2b) with adjustments for body mass index
diabetes (no/yes; self-reported diabetes and/or use of antidiabetic medication and/or non-fasting glucose concentration at HUNT3 &gt; 11 mmol/L)
hypertension (no/yes; systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg and/or self-reported use of antihypertensive medication)
The Step3 model included both RA and CRP with the same adjustments
To assess potential bias due to dichotomization of CRP concentrations at 3 mg/L
a Step3 sensitivity analysis was performed using 5 mg/L as cut-off instead
Another sensitivity analysis included RA and CRP in the same model
but without the adjustments mentioned above
A second Step3 sensitivity analysis included further adjustments for previous self-reported cancer or chronic respiratory disease (asthma/chronic obstructive pulmonary disease)
the Step4 models included either RA (Step4a)
Both lactoferrin and neopterin concentrations were highly skewed and were transformed using natural logarithms to achieve proportional hazards
Dichotomization was not necessary to this end
The Step5 model included RA and all 3 biomarkers of inflammation and was adjusted as described above
Hazard ratios (HR) of the models are given with robust 95% confidence intervals (CI)
Model fit including proportionality of hazards and the appropriate functional form of continuous variables was assessed using Schoenfeld and Martingale residuals
Models within the main study or within the nested cohort study were compared using the Akaike (AIC) and Bayesian information criteria (BIC)
where a smaller numerical value indicates better fit
the independent associations with all-cause mortality of each of the explanatory variables presence of rheumatoid arthritis and C-reactive protein concentration ≥ 3 mg/L were investigated
the direct association with all-cause mortality of rheumatoid arthritis was investigated ()
as well as the indirect effect of rheumatoid arthritis mediated by inflammation
using C-reactive protein concentration ≥ 3 mg/L as biomarker ()
Both final models were adjusted for body mass index
Mortality rates were significantly higher in RA patients than controls (27% vs
Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41598-022-21977-9#Tab2">2</a> shows results from the Cox regression analyses
in which age differences between RA patients and controls were accounted for using age as time variable and sex was included as a stratification variable
both RA and CRP ≥ 3 mg/L were significantly associated with all-cause mortality in the Step1 models and the Step2 models (additionally adjusted for body mass index
HR became slightly lower following adjustment but were still clearly within the confidence intervals from the Step1 models
both variables were independently associated with mortality when tested separately
In the Step3 model including both RA and CRP
the HR for CRP hardly changed compared to the Step2b model and there was no significant interaction between RA and CRP (p = 0.64)
the HR for RA fell from 1.34 in the Step2a model to 1.25 and RA was now barely significant (p = 0.048)
consistent with the hypothesis that inflammation as captured by CRP may be a mediator of the increased mortality associated with RA
The wide CI are probably related to the low number of RA cases
There was no significant interaction (− 2% (− 29%
The results from the Step3 sensitivity analysis using CRP ≥ 5 mg/L as cut-off were essentially the same as with CRP ≥ 3 mg/L (RA; HR = 1.23 (0.99
The change in significance for RA may be a false-negative result because the number of RA patients with CRP ≥ 5 mg/L (n = 89
31%) was lower than the number with CRP ≥ 3 mg/L (n = 128
In the sensitivity analysis including both RA and CRP ≥ 3 mg/L without adjustment for classical CV risk factors
these results indicate that the influence of the classical CV risk factors on the associations of RA and CRP on mortality was small
There were no changes in the HR for RA nor CRP in the Step3 model including additional adjustments for previous cancer or chronic respiratory disease
In the nested cohort study, Cox regression showed that RA, CRP ≥ 3 mg/L, lactoferrin, and neopterin were all significantly associated with mortality when tested separately in adjusted models (Models 4a, 4b, 4c, and 4d, Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41598-022-21977-9#Tab2">2</a>)
When RA and all three biomarkers were included in the same model
consistent with inflammation as indicated by CRP and neopterin being mediators of increased mortality associated with RA
Model fit including proportionality of hazards was good or acceptable for all Cox regression models
Within the main study and the nested cohort study
RA and inflammation as captured by CRP and neopterin were significantly associated with all-cause mortality
Mediation analysis showed that the overall excess relative risk for all-cause mortality of having RA was 38%
and approximately a quarter of this was mediated by inflammation
other factors related to RA accounted for a substantial part of the excess mortality risk
even when adjusting for classical CV risk factors
The novelty of the study lies in this quantification of the impact on mortality mediated by inflammation
similar genetic investigations related to other important causes of death in RA like cancer have not been performed
which may have been captured by the neopterin measurements
neopterin may also be considered a marker of the results of inflammation
Our study was not aimed at risk prediction
so we are not advocating measurement of neopterin in RA patients for clinical reasons
Such non-pharmacologic interventions may also improve other CV risk factors like blood pressure and lipids
Using definitions of RA remission with a strong emphasis on achieving minimal levels of general inflammation may also be warranted
We therefore cannot exclude that participant selection bias may have influenced our results
Another possible limitation of our study is that CRP may not be a sufficiently good marker of inflammation
even if it is used clinically by rheumatologists to assess levels of inflammation and disease activity in RA patients
We cannot exclude that adding more or other inflammation markers than CRP in the main study would have reduced the unexplained part of the association with RA
Information about medication was not available
RA-specific medications would not have been useful in our analysis because of collinearity with presence or absence of RA
similar to other RA-specific variables like disease activity
Adjusting for use of other medications including drugs for CVD like statins could have been useful because prescription policies may differ between RA patients and controls
the present study showed that approximately a quarter of the excess relative mortality risk of RA was mediated by inflammation
The findings underscore the importance of employing all available modalities to reduce inflammation
including carefully selected medications and lifestyle changes
reducing inflammation alone cannot be expected to abolish excess mortality rates in RA
Data from the HUNT Study are available upon reasonable request from the HUNT Research Centre (<a href="https://www.ntnu.edu/hunt/data">https://www.ntnu.edu/hunt/data</a>)
following approval from the Regional Research Ethics Committee
restrictions apply to the availability of the data for the present paper
which were used under license for the current study and are not publicly available
Rheumatoid arthritis and excess mortality: Down but not out
A primary care cohort study using data from Clinical Practice Research Datalink
Mortality following new-onset rheumatoid arthritis: Has modern rheumatology had an impact?
Cause-specific mortality in a large population-based cohort of patients with rheumatoid arthritis in Italy
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Liff, M. H., Hoff, M., Wisloff, U. &amp; Videm, V. Reduced cardiorespiratory fitness is a mediator of excess all-cause mortality in rheumatoid arthritis: The Trøndelag Health Study. RMD Open 7, e001545. <a href="https://doi.org/10.1136/rmdopen-2020-001545" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1136/rmdopen-2020-001545">https://doi.org/10.1136/rmdopen-2020-001545</a> (2021)
Higher mortality rates associated with rheumatoid arthritis in Saskatchewan
Cardiovascular risk and mortality in rheumatoid arthritis compared with diabetes mellitus and the general population
Causes of death in rheumatoid arthritis: How do they compare to the general population?
Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis
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Cardiovascular effects of approved drugs for rheumatoid arthritis
Targeting inflammation in atherosclerosis - from experimental insights to the clinic
Markers of inflammation and cardiovascular disease: Application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association
Sienkiewicz, M., Jaśkiewicz, A., Tarasiuk, A. &amp; Fichna, J. Lactoferrin: An overview of its main functions, immunomodulatory and antimicrobial role, and clinical significance. Crit. Rev. Food Sci. Nutr. 8, 1–18. <a href="https://doi.org/10.1080/10408398.2021.1895063" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1080/10408398.2021.1895063">https://doi.org/10.1080/10408398.2021.1895063</a> (2021)
Multiple inflammatory markers in patients with significant coronary artery disease
Lactoferrin is a novel predictor of fatal ischemic heart disease in diabetes mellitus type 2: Long-term follow-up of the HUNT 1 study
Neopterin derivatives—a novel therapeutic target rather than biomarker for atherosclerosis and related diseases
Shirai, R. et al. Neopterin counters vascular inflammation and atherosclerosis. J. Am. Heart Assoc. 7, e007359. <a href="https://doi.org/10.1161/JAHA.117.007359" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1161/JAHA.117.007359">https://doi.org/10.1161/JAHA.117.007359</a> (2018)
Neopterin and atherosclerotic plaque instability in coronary and carotid arteries
Self-reported diagnosis of rheumatoid arthritis or ankylosing spondylitis has low accuracy: Data from the Nord-Trøndelag Health Study
2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative
An enzyme linked immunosorbent assay for measurements of lactoferrin in duodenal aspirates and other biological fluids
Med4way: A Stata command to investigate mediating and interactive mechanisms using the four-way effect decomposition
Rostami, S., Hoff, M., Dalen, H., Hveem, H. &amp; Videm, V. Genetic risk score associations for myocardial infarction are comparable in persons with and without rheumatoid arthritis: The population-based HUNT study. Sci. Rep. 10, 20416. <a href="https://doi.org/10.1038/s41598-020-77432-0" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41598-020-77432-0">https://doi.org/10.1038/s41598-020-77432-0</a> (2020)
Autonomic function and rheumatoid arthritis: A systematic review
Yu, Z. et al. Association between inflammation and systolic blood pressure in RA compared to patients without RA. Arthritis. Res. Ther. 20, 107. <a href="https://doi.org/10.1186/s13075-018-1597-9" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s13075-018-1597-9">https://doi.org/10.1186/s13075-018-1597-9</a> (2018)
Serum level of neopterin is not a marker of disease activity in treated rheumatoid arthritis patients
Differences in atherosclerotic coronary heart disease between subjects with and without rheumatoid arthritis
Carotid plaque characteristics and disease activity in rheumatoid arthritis
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The role of exercise in the management of rheumatoid arthritis
Excess mortality emerges after 10 years in an inception cohort of early rheumatoid arthritis
Langhammer, A., Krokstad, S., Romundstad, P., Heggland, J. &amp; Holmen, J. The HUNT study: Participation is associated with survival and depends on socioeconomic status, diseases and symptoms. BMC. Med. Res. Methodol. 12, 143. <a href="https://doi.org/10.1186/1471-2288-12-143" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/1471-2288-12-143">https://doi.org/10.1186/1471-2288-12-143</a> (2012)
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and Oddrun Storvold Storrø provided excellent technical assistance
The Trøndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences
NTNU—Norwegian University of Science and Technology)
and the Norwegian Institute of Public Health
The study was supported by The Liaison Committee for Education
Research and Innovation in Central Norway (Samarbeidsorganet
NTNU–Norwegian University of Science and Technology (project 82600805 to ISH)
and the Research Council of Norway (project 249944 to VV)
Open access funding provided by Norwegian University of Science and Technology
Department of Clinical and Molecular Medicine
NTNU-Norwegian University of Science and Technology
Department of Immunology and Transfusion Medicine
Department of Neuromedicine and Movement Science
V.V.: Substantial contributions to the conception and design of the work
Drafting the work and revising it critically for important intellectual content
I.S.H.: Substantial contributions to the acquisition
Revising the work critically for important intellectual content
M.H.L.: Substantial contributions to the interpretation of data for the work
M.H.: Substantial contributions to the conception of the work and interpretation of data for the work
All authors have approved the final version to be published
and agree both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work
even ones in which the author was not personally involved
and the resolution is documented in the literature
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Insolvency administrator and the mill's new management could present the business and debt settlement plan at the end of January or February
Slovenia's publication and packaging paper manufacturer Vipap Videm Krško is currently running through compulsory settlement proceedings
the Czech company Vipap CZ filed the action for enforcement with the competent court in Krško last September and the insolvency proceedings were officially opened on 3 November
 At the start of December Vipap CZ reported that Vipap Videm was "now entering a crucial part of the compulsory settlement process with its creditors." This process
which began in September had allowed the company "to go through debt restructuring and a review of of operating costs"
and to ready itself for the restart of production with a new product portfolio
Vipap Videm resumed production of publication paper on one paper machine at the start of December
Packaging paper production on a second PM followed a couple of days later
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The goal of the Time to Raise initiative is to change the financial landscape for startups
Cilia Holmes Indahl from Eqt Partners is a mentor for the Time to Raise programme
The reason being that she wants to ensure that more women start companies - but also that there is nothing quite as "sexy" as a good business model
It might be a model with an "impact" on the world and has a financial plan that will work in the market
This is also the thinking behind the Eqt Foundation
and we want to enter at a very early stage to ensure that the innovations reach the market,” says Cilia Holmes Indahl
One of the attendees of the Time to Raise programme is Maria Barklund
a company that develops fast and accurate diagnosis of infections
The test can be used directly at health centers or at home
and provides reliable test results within an hour
“With this test we can streamline the flow of care and implement the right treatment quicker and prevent the spread of infections and antibiotic resistances
The technology is based on seven years of research in chemical and bionanotechnology,” she says
Maria sees the fact that Time to Raise focuses on female startups as an advantage
This has created a predefined image of what an entrepreneur is
“But it feels like a change is underwp&nbsp;to follow a path that someone has taken before
which I think many young women will have in 10­–15 years
But then an extraordinary effort must be made for a period of time
such as Time to Raise provide the opportunity for new ideas to take place
the founders get to meet both mentors and lecturers
They can also book separate meetings with each of them - an opportunity that Maria Barklund sees as very difficult to achieve otherwise
“It is a chance to exchange questions and answers with someone who has experienced different parts of the business
So I booked a follow-up appointment with her.”
they discussed various business models and issues that Videm faced
Cilia introduced Videm to an investment team at the Eqt Foundation
“I did not know that Eqt entered at such an early stage
This was something very tangible that came out of the programme
Had I not been interested in business models
and had Cilia not been as responsive and curious as she was
this opportunity probably would never have happened,” says Maria Barklund
To be a mentor is to contribute and complement your own experience towards other people's ideas
asking the right questions that allow a business model to become more "bullet proof"
Maria Barklund agrees: “I think it's super important
The reason I applied for Time to Raise was because good people were involved
It is not only an opportunity to receive information from talented lecturers and mentors
but also a chance to be able to share insights with other founders
“Most people who start companies go through the same experiences
Being able to share those experiences with others makes you feel less alone,” says Maria
The company Videm has recently closed its first investor round and withdrawn just over five million SEK
it will probably be time to recruit and build further
“I hope that everyone wants to get involved in issues that are important
it is important that you contribute in a way that fulfills you.”
Being an entrepreneur is more important than ever
Cilia Holmes Indahl thinks that new technology is really needed right now
as well as innovations that can contribute to and create new jobs across society
“We have a responsibility to encourage young people to dare to take initiatives to embark on a journey like this
BookmarkAdd News to dashboardThe new owner of Slovenian paper mill Vipap Videm Krško
is investing more than CZK250m (approximately €10m) in the company
The money will be invested in the production of paper for food packaging
The new product range will comprise paper bags
Recent high-level events organised in the framework of the Slovenian Presidency of the Council of the EU looked at topics close to the ambitions and goals of the Long-term vision for rural areas for 2040
which calls for a cooperation between different policies such as infrastructure
They welcomed future cooperation and further efforts to find solutions for the integrated development of the European countryside
Strengthening the dialogue between the urban and rural areas<a href="/en/news/2021-12-20-combining-european-funds-towards-the-vision-for-rural-areas-in-2040/#_ftn3" name="_ftnref3" class="ss-broken">[3]</a> was the topic of the informal meeting of EU agriculture ministers (5-7 September 2021)
Key challenges are the integration of agriculture and non-agricultural activities in new rural settlements and society's expectations towards rural areas
which are expected to provide their inhabitants with living standards similar to those in cities
to contribute to natural ecosystem services and other public goods
The ministers discussed how member states see the coexistence of urban and rural areas
how to solve challenges and prevent conflicts
They agreed that rural areas are a multi-purpose space in which various activities coexist and complement each other
The social role of rural areas needs to be redefined and at the same time supported in all its diversity and quality
which will bring together politicians at all levels and businesses with the aim of developing concrete activities contributing to rural development
Good practice examples of digitalisation in various economic and social sectors showed how the business sector is already developing future-orientated solutions for the countryside and small cities: for example
Toyota Adria is developing innovative mobility services for rural areas
An outstanding example from the social sector
One of the messages from all these events is that the use of different EU funds can make the long-term vision a reality
The new CAP is one of the key sources of EU funding for rural areas
and the European Regional Development Fund
the Cohesion Fund and the European Social Fund Plus can provide significant investments in people and infrastructure in rural areas
The Recovery and Resilience fund and European Investment Bank support can be used to cover existing investments gaps
<a href="/en/news/2021-12-20-combining-european-funds-towards-the-vision-for-rural-areas-in-2040/#_ftnref1" name="_ftn1"></a>
The Smart Silver Village concept is bringing together different EU funds to address the growing need for long-term elderly care in the countryside - close to people’s homes
The Slovenian countryside has an aging population and villages face an increasing lack of services
The LAG Posavje joined forces with other Slovenian LAGs to design smart solutions that would keep the countryside vital
The Smart Silver Village concept was developed in the frame of the LEADER cooperation project ‘Smart Villages for Tomorrow’<a href="/en/news/2021-12-20-combining-european-funds-towards-the-vision-for-rural-areas-in-2040/#_ftn1" name="_ftnref1" class="ss-broken">[1]</a>
a study examined different smart living systems for older people with long-term care needs
various concepts of housing units could be developed across Slovenia and beyond
Smart housing systems include health and social services upgraded with digital
telecommunication’s technologies and green innovations (e.g
The concept of Smart Silver Village include also day centres for elderly people whose relatives are absent during the day due to their jobs. A first day centre was already built in Videm<a href="/en/news/2021-12-20-combining-european-funds-towards-the-vision-for-rural-areas-in-2040/#_ftn2" name="_ftnref2" class="ss-broken">[2]</a>
co-financed by the European Fund for Regional Development and the Krško Municipality
qualified local jobs were created for young people.&nbsp;&nbsp;
Project Smart Village also encouraged the implementation of another pilot project
which offers integrated health and social care for elderly people at home
This project was funded by European Social Fund
In the future the Krško municipality is planning to build other ‘silver villages’ with support from a combination of EU funds
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neopterin and lactoferrin are biomarkers of atherosclerotic disease
We aimed to assess changes in these biomarkers after conservative and surgical weight loss interventions in individuals with morbid obesity
to evaluate associations between biomarker changes and changes in body mass index and HbA1c
and to study associations between changes in the biomarkers
neopterin and lactoferrin were measured before and after conservative weight loss intervention and bariatric surgery
137 individuals (mean age 43 years) were included
Body mass index decreased from 42.1 kg/m2 to 38.9 kg/m2 after the conservative intervention
and further to 30.5 kg/m2 after bariatric surgery
All biomarkers decreased after the conservative weight loss intervention
C-reactive protein and lactoferrin continued to decrease following bariatric surgery whereas neopterin remained stable
After adjustments for change in body mass index and HbA1c
all biomarkers decreased significantly after the conservative weight loss intervention
whereas none changed after bariatric surgery
There were no consistent correlations between changes in C-reactive protein
biomarkers of atherosclerosis decreased after weight loss interventions but had different trajectories
a marker related to atherosclerotic plaque stability
decreased after conservative weight loss but not following bariatric surgery
Less is known about changes in other biomarkers of inflammation such as neopterin and lactoferrin after weight loss
The hypotheses for the study were that because the included biomarkers represent different aspects of inflammation
their changes following conservative and surgical weight loss interventions would not necessarily follow the same patterns and that the changes could be different in the two treatment periods
we hypothesized that the biomarker changes may be associated with changes in BMI or HbA1c
which were considered as available proxies of changes in adiposity and glucose tolerance
The present study had the following aims: (1) To assess changes in the biomarkers CRP
and neopterin after conservative and surgically induced weight loss in individuals with MO and to compare the changes in the two treatment periods (2) To assess whether the biomarker changes in the two treatment periods were associated with changes in BMI and HbA1c in multivariable analysis
and to compare the associations in the two treatment periods
(3) To study the associations between changes in CRP
neopterin and lactoferrin after weight loss
individuals with blood samples analysed for biomarkers and with complete data on weight
hypertension and chronic obstructive pulmonary disease (COPD)
Information from three visits was used; a first visit to the hospital
a second visit around 5 months later after the conservative weight loss intervention and before the bariatric surgery
Exclusion criteria were major psychiatric disorders
and serious somatic disorders not judged as obesity-related
conditions that would preclude usual weight loss treatment at the clinic
The participants thus represented the usual selection of individuals treated at the clinic and were receiving standard care for any comorbidities
They were asked to report any ongoing illnesses
and blood sampling was performed during routine visits when they reported to be well
Information about comorbidity was provided by the participant on a case report form
This information was reviewed by a physician with full access to the hospital records
All included participants started with three hour-long consultations with three health professionals; a nurse
which included personalized advice on diet and physical activity
These consultations were usually scheduled in three separate weeks to give the participant time to implement suggested changes
all participants were enrolled in a patient group with weekly four-hour meetings during seven consecutive weeks
The meetings included group counseling together with other participants with morbid obesity
and were led by nurses specialized in obesity
The participants were recommended to eat more fiber and protein
and to distribute their food intake into 4–6 meals each day with 2–4 hour intervals between meals
Advice on specific dishes was individualized by a nutritionist based on the individual’s former diet and food preferences
21 days before the second study visit the participants were advised to follow a “crisp bread diet” containing 1000 kcal/day
The recommendations for this diet was intake of six pieces of crisp bread with low-fat high-protein topping (cheese
a small dinner plate (meat or fish with vegetables)
or avocados) and free amounts of beverages without calorie content (preferentially above 2 litres)
the participants could use meal replacement powder giving 800–900 kcal with vegetables
All participants were told that acceptance to the clinic’s public
free-of charge bariatric surgery program partly depended on their adherence to the given advice
The second study visit took place after the conservative weight loss program
The third visit was a postoperative follow-up at the outpatient clinic for MO about six months after bariatric surgery
The present study used a subset of the variables in the main study
calculated as the weight in kilograms divided by the square of the height in meters)
comorbidities (chronic obstructive pulmonary disease
HDL cholesterol and HbA1c were registered in addition to serum concentrations of the inflammatory biomarkers CRP
neopterin values above 10 nmol/L are evaluated as pathological
lactoferrin values were below &lt;250 ug/L (V Videm
low- and high-density lipoprotein (LDL and HDL
respectively) cholesterol were analysed using standard methods at Innlandet Hospital Trust Gjøvik
Data are given as mean (standard deviation – SD) or number (percentage)
Statistical analysis was performed using mixed models
The time variable was coded as time 0 (first visit)
23 weeks (second visit) and 49 weeks (follow-up visit after bariatric surgery)
Mixed models allow for simultaneous analysis of the three repeated (i.e
correlated) measurements in each individual and direct comparison of the changes after conservative weight loss with the changes following bariatric surgery
It also allows for individual trajectories of the variables in each individual
and different numbers of participants included at each time point due to attrition during follow-up
These are realistic assumptions for biomarkers of inflammation
where it is unrealistic that all participants will complete all steps of treatment
Data were first analysed in univariate models with CRP
in order to investigate the observed values and changes after the two weight loss interventions
Each biomarker was thereafter analysed in a multivariable model including BMI and HbA1c to investigate associations of the biomarker changes with changes in adiposity and glucose tolerance
also including adjustments for age and sex to avoid confounding due to increased low-grade inflammation with older age or to sex-related differences
To evaluate whether the associations between each biomarker and BMI or HbA1c were different after the conservative and the surgical weight loss interventions
interaction terms with time were evaluated
Model fit was assessed using residual plots
Pearson’s correlation coefficients were calculated between changes in CRP
neopterin and lactoferrin as well as between changes in each biomarker and changes in BMI or HbA1c after the two weight loss interventions
This method does not take within-person correlation into account
unadjusted mixed models including one biomarker as the dependent variable and another as the independent variable as well as an interaction term with time were also analysed
thus accounting for within-person correlation
unadjusted mixed models including each biomarker as the dependent variable and either BMI or HbA1c as the independent variable and an interaction term with time were analysed to assess unadjusted associations between changes in each biomarker and changes in adiposity or glucose tolerance
Overall association in each of these models was evaluated using the between-person Snijders/Bosker R2 for mixed models
P-values &lt; 0.05 were considered significant
To assess the robustness of the findings in the analyses to investigate associations of the biomarker changes with changes in BMI and HbA1c
we performed sensitivity analyses with additional adjustment for smoking (coded as ever
former or present smoker) or gastric sleeve vs
We also analysed models where body weight was included instead of BMI
The study was approved by the Regional Committee for Medical and Health Research Ethics South East Norway (reference 2012/966) and conducted in accordance with the Declaration of Helsinki
Written informed consent was obtained from all participants included in the study
A total of 137 participants of which 135 had complete baseline data for each of the three biomarkers (78% females) with a mean age of 43 years and a mean BMI of 42 kg/m2 were included (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41598-019-54107-z#Tab1">1</a>)
The levels of inflammatory biomarkers were slightly increased at inclusion
A third of the participants had hypertension and a fifth of the participants had diabetes mellitus
but few of the included participants had developed atherosclerotic disorders as acute myocardial infarction or stroke
</a>Biomarkers of inflammation, body mass index and HbA1c (observed values). Data are given as means with 95% confidence intervals. Statistical testing with mixed models.
</a>Biomarkers of inflammation adjusted for sex
age and changing body mass index and HbA1c
Data are given as means with 95% confidence intervals
The sensitivity analyses showed that the associations of the biomarker changes with changes in BMI or HbA1c were essentially unaltered with adjustment for smoking or when considering the type of operative procedure
When body weight was used in the models instead of BMI
This finding indicates that changes in BMI rather than changes in weight were more closely related to the biomarker changes
In this prospective study of individuals with MO
the levels of three biomarkers of inflammation were reduced in the blood after major weight loss
We observed different patterns after conservative and surgical weight loss
and in this regard it is notable that neopterin was significantly improved after a conservative weight loss intervention
the assayed biomarkers are not specific to atherosclerosis or other single endpoints
The pattern of change after a surgical weight loss intervention was different and did not depend on the operative method (gastric sleeve vs
The amount of excess weight lost after the intervention was much larger than the amount lost after the conservative weight loss intervention
the reductions in CRP and lactoferrin were not larger
and neopterin did not change after the surgical weight loss intervention
After adjustment for changes in glucose tolerance and BMI
the changes in inflammation after surgical weight loss were not significant
The study design precludes drawing of conclusions regarding precise mechanisms for the observed biomarker changes
The fact that models including BMI rather than weight changes showed better fit
may indicate that the mechanisms are not induced by weight changes alone but are more strongly related to differences in adiposity
Changes in low-grade inflammation after obesity surgery might have a different aetiology than changes after conservative weight loss interventions
These issues need further investigation in studies with different designs
two different methods to lose weight do not have an equal impact on neopterin
and inclusion of more biomarkers of inflammation than CRP might be important in future studies of weight loss
The choice of weight loss intervention should probably be based on more factors than weight alone; including comorbidity load
body composition and possibly genetic markers and biomarkers
Different biomarkers of inflammation could be tested for clinical utility in this setting
and our study was not designed to investigate the usefulness of each biomarker on specific endpoints
and all bariatric surgery was performed by the same three experienced surgeons
A weakness is that all participants underwent their two periods of weight loss intervention in the same order with the conservative intervention first
It is therefore possible that the changes during the conservative weight loss period (e.g
the change in neopterin) were caused by this intervention coming first
Our findings should therefore ideally be re-examined in a study where participants are randomized to conservative or surgical weight loss interventions
Data regarding adherence to the conservative weight loss protocol were not available
The observed changes in weight during this period indicate that most participants have followed the advice to a degree giving measurable effects
The generalizability of the findings to individuals with a BMI under 35 kg/m2 is unknown
Detailed examinations of body composition might have been of interest to interpret the changes but were unfortunately not available
the study might have false-negative findings due to the relatively large individual variation in concentrations of inflammatory markers
were all significantly reduced in individuals with MO after a year with extensive weight loss
The changes were more prominent after conservative weight loss than after surgery-induced weight loss
Changes in CRP were associated with changes in BMI
whereas neopterin and lactoferrin did not show strong associations with HbA1c or BMI
Our data indicate that these inflammatory markers have different trajectories during weight loss and give information about different aspects of inflammation
Case report forms (CRFs) on paper were used for the collection of the clinical data
The data were transferred manually to SPSS for statistical analyses
The data files are stored by Innlandet Hospital Trust
on a server dedicated to research and with security according to the rules given by The Norwegian Data Protection Authority
The data are available on request to the authors
but restrictions apply to the availability of these data according to Norwegian law so they are not publicly available
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The project was funded by Innlandet Hospital Trust
NTNU – Norwegian University of Science and Technology
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The lectin complement pathway is suggested to play a role in atherogenesis
MBL/ficolin/collectin-associated serine protease-3 (MASP-3) and MBL/ficolin/collectin-associated protein-1 (MAP-1) are molecules related to activation of the lectin complement pathway
We hypothesized that serum levels of these molecules may be associated with the incidence of myocardial infarction (MI)
In a Norwegian population-based cohort (HUNT2) where young to middle-aged relatively healthy Caucasians were followed up for a first-time MI from 1995–1997 through 2008
the 370 youngest MI patients were matched by age (range 29–62 years) and gender to 370 controls
After adjustments for traditional risk factors
the two highest tertiles of PTX3 and the highest tertiles of ficolin-2 and MASP-3 were associated with MI
with odds ratios (95% confidence interval) of 1.65 (1.10–2.47) and 2.79 (1.83–4.24) for PTX3
ficolin-3 and MAP-1 were not associated with MI
In a multimarker analysis of all associated biomarkers
PTX-3 and MASP-3 enhanced prediction of MI compared to the traditional Framingham risk score alone (AUC increased from 0.64 to 0.68
These results support the role of complement-dependent inflammation in the pathophysiology of cardiovascular disease
early molecular or biochemical warning signals are urgently needed
the mechanisms that drive the persistent non-resolving inflammation in the vessel wall remain incompletely understood
The complement system is an intricate system consisting of a complicated network of mediators with many interactive effects
We hypothesized that PRRs and their associated proteins in the lectin pathway regulate the immune response in the pathogenesis of atherosclerosis
the aim of the present study was to investigate the association between serum levels of PTX3
MASP-3 and MAP-1 in young and middle aged relatively healthy individuals from the general Norwegian population with the future risk of MI
These might represent novel biomarkers for CVD and potential targets for the development of future treatment strategies
Baseline characteristics of cases and controls are displayed in <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/srep43045#Tab1">Table 1</a>
Conventional cardiovascular risk factors were more frequent among cases: They had higher BMI
and family history of myocardial infarction
Cases were more often current smokers and had higher Framingham risk scores
Mean age for MI was 53 years (range 29–62)
26 (3.5%) and 10 (1.4%) patients had missing data on smoking and creatinine
missing values for background characteristics were generally low (&lt;0.2%)
the R2-values were generally low (&lt;0.1)
indicating that the variables included explained a fraction of the plethora of variation in biomarker concentration
PTX3 and MAP-1 were not associated with any risk factors
ficolin-3 (p = 0.03) and MASP-3 (p = 0.03) were associated with BMI
and ficolin-2 was also associated with smoking (p = 0.01)
Ficolin-1 was associated with sex (p = 0.002) and creatinine (p = 0.03)
Serum concentrations of the biomarkers are displayed in <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/srep43045#Tab2">Table 2</a>
PTX3 (p &lt; 0.001) and ficolin-2 (p &lt; 0.001) were higher among cases
also after adjustments for classical risk factors
MASP-3 was lower among cases (p = 0.03) and this remained significant after adjustments for conventional CVD risk factors
PTX3 was weakly correlated with ficolin-2 (Rho = 0.09
MASP-3 was further correlated with ficolin-1 (Rho −0.1
MAP-1 was correlated with ficolin-2 (Rho 0.14
</a>Comparison of the area under the receiver-operating characteristic curve (AUC) of the clinical model based on the Framingham risk score
with the model including pentraxin-3 and MBL/ficolin/collectin-associated serine protease-3
we found that higher concentrations of PTX3 and ficolin-2
and lower concentrations of MASP-3 were associated with increased risk of MI in middle-aged relatively healthy individuals
independent of conventional CVD risk factors
The available evidence therefore suggests that increased levels of PTX3 in patients with CVD reflects a protective physiologic response
The missing link between the genetic variants determining PTX3 and ficolin-2 levels with the risk of MI suggests that they act as markers of active atherosclerosis and complement activity rather than causal factors
the lack of association of ficolin-2 to the risk of MI in the multimarker analysis may suggest that the information added by ficolin-2 was at least partially conveyed by the other markers
Low levels of MASP-3 may be related to decreased synthesis or increased turnover
we cannot exclude that MASP-3 acts as a marker for other causal relationships
It has been shown that MASPs interact with ficolins
altering the effect of the complement system
An effect of MASP-3 mediated through interactions with other molecules can therefore not be excluded
The authors suggested a potential role through non-complement pathways
The mechanisms underlying the association between lower MASP-3 concentrations and an increased risk of MI warrants further investigation
The purpose of this study was not to evaluate the predictive performance of selected biomarkers
ficolin-2 and MASP-3 may uncover potential new causal mechanisms in the development and progression of coronary heart disease and risk for MI
lead to the generation of new hypotheses and suggest improvements to existing explanatory models
Atherogenesis is characterized by multiple distinct pathways and molecular mechanisms
and our findings underscore the importance of the innate immune response and complement activation
A step further would be to investigate the causal relationships underlying the present associations
The novel markers may be potential targets that can be included in a multimarker panel for predicting CVD and identifying individuals at higher risk of MI
Our study has some limitations: We did not have accurate times to MI to our disposal
and despite exclusion of patients with clinical CVD
the group middle-aged relatively healthy individuals may constitute a heterogeneous study population with subclinical atherosclerosis at different stages
elevated ficolin-2 and low MASP-3 concentrations were associated with increased risk of future MI in young to middle-aged relatively healthy Caucasians
Higher PTX3 and ficolin-2 concentrations may indicate higher complement activity
underlying mechanisms and potential use in a predictive setting merits further investigation
our findings support the involvement of complement-dependent inflammation in the pathophysiology of cardiovascular disease
All methods were carried out in accordance with relevant guidelines and regulations
The study protocol was approved by the Regional Research Ethics Committee in Medicine
Central Norway (project numbers 157–1997 dated 06/11/1997 and 2009.1852 dated 11/20/2009) and the Data Inspectorate of Norway
Informed consent was obtained from all HUNT2 participants
Data on MI hospitalization was collected from the two primary hospitals in the county of Nord-Trøndelag: Levanger Hospital and Namsos Hospital
From 1995 until 2000 data were registered retrospectively
and from 2001 registration has been done prospectively
The European Society of Cardiology/American College of Cardiology guidelines were used for verification of MI diagnosis
The criteria are elevated troponin T or troponin I together with at least one of the following: (1) symptoms consistent with myocardial infarction and/or (2) ECG changes with development of significant Q wave and/or (3) ECG changes consistent with ischemia (ST segment elevation or depression)
A positive family history for coronary heart disease was defined as MI before 60 years in a first-degree relative
All assays were optimized for automated analysis in the 384 well format on Biomek FX (Beckman Coulter
Due to non-normal distribution of several variables
the Mann-Whitney U test was used to evaluate differences in continuous variables
The Chi square test was used to compare categorical variables
Linear regression with robust standard errors was used to analyse how clinical variables were associated with serum concentration of the biomarkers
hypercholesterolemia (yes/no) and creatinine
either logarithmic transformation or Box-Cox transformation was performed
and extreme outliers were removed from the final models if they substantially altered the results
Spearman correlation analysis was used to evaluate how the different biomarkers were related to each other
Associations between biomarker concentration and risk of MI were investigated using logistic regression
Traditional risk factors included in the final models were sex
the improvement in predictive utility was explored with an analysis of the AUC
continuous net reclassification index and integrated discrimination index
Prediction of MI using the Framingham risk score alone was compared to a model combining the Framingham risk score with significant biomarkers from the multimarker analysis
and results are presented as medians or odds ratios with 95% confidence intervals
P-values below 0.05 were considered statistically significant
All analyses were performed with Stata/MP for Mac
version 3.2.2 (Foundation for Statistical Computing
ficolin-2 and lectin pathway associated serine protease MASP-3 as early predictors of myocardial infarction - the HUNT2 study
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The HUNT Study is collaboration between HUNT Research Centre (Faculty of Medicine
NTNU - Norwegian University of Science and Technology)
We are grateful to the people of Nord-Trøndelag and the personnel at the HUNT Biobank
The Department of Research and Development and clinicians at the Medical Department
are acknowledged for their help with data collection and diagnosis validation
Jesper Andresen for excellent technical assistance
This work was supported by grants from The Norwegian Council on Cardiovascular Diseases
The Danish Council for Independent Research
Rigshospitalet and The Svend Andersen Research Foundation
Inga Thorsen Vengen and Tone Bull Enger: These authors contributed equally to this work
Norwegian University of Science and Technology
contributed to the interpretation of the data
revised the manuscript critically for important intellectual content
All authors approved the final version of the manuscript and are accountable for the accuracy and integrity of the work
The authors declare no competing financial interests
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